Disease/Drug of interest: Raltegravir and Human Immunodeficiency Virus (HIV)
Motivation and Background:
HIV stands for human immunodeficiency virus and spreads through contact with bodily fluids, such as blood, semen, breast milk, and vaginal liquids, from infected individuals [1]. After HIV initially enters the body, it spreads to the lymphoid tissues through virus replication; if left untreated, HIV begins a period of “microbial latency,” in which it replicates and slowly degrades the body’s immune system [2]. While there are three stages of HIV progression, most patients with HIV are not diagnosed until they reach Stage 3 [1]. In this stage, HIV develops into acquired immunodeficiency syndrome, more commonly known as AIDS [1]. AIDS can develop into many other health conditions, such as pneumonia, thrush, fungal infections, TB, cancer, and brain illnesses, and commonly leads to death, if left untreated [1]. As shown in Figure 1, without any kind of HIV medication, HIV-infected individuals experience about ten years of microbial latency and then die after eleven years upon being initially infected by HIV [3]. HIV is a worldwide problem, as the World Health Organization and Joint United Nations Program on HIV/AIDS estimate that there are 36.9 million people infected with HIV currently, and 39 million people infected with HIV have died since HIV’s discovery in 1981 [4]. Of these numbers, Sub-Saharan Africa adds about 70% of new cases to the worldwide total, 60% of infected people do not have the proper healthcare access to obtain HIV treatment, and 46% do not know that they have HIV, due to inadequate healthcare services [4]. One of the main issues with preventing and treating HIV is that HIV outbreaks are more prevalent in economically disadvantaged areas, so access to HIV diagnosis and treatment is most limited in the areas with the highest rates of HIV infection [4]. Exacerbating this problem, HIV cannot be cured; its symptoms can only be lessened and controlled through the use of antiretroviral therapy [1]. However, antiretroviral therapy is effective at treating HIV symptoms and decreasing the chance of a HIV-related death.
Figure 1) Without HIV medication, CD4 T cells deplete by half in six weeks and patients typically die in eleven years. Of the 6 types of HIV drugs, raltegravir, marketed as Isentress by Merck and Company, introduced the Integrase Strand Transfer Inhibitors (INSTI) category [3]. ARV drugs in this category work by blocking the function of the integrase enzyme [5]. One of raltegravir's major benefits is that it can be taken not only by people who have HIV strains that are resistant to many other pre-existing ARV drugs, but also by those who have just been diagnosed [10].
Target Information:
Size: 32 kDa Location: Integrase is expressed by HIV's DNA and functions in CD4 T lymphocytes-white blood cells that prevent the body from infections-once it is expressed. Function in a normal cell: When this enzyme normally functions, it binds HIV DNA to healthy DNA in a two-step process; first, it separates the viral DNA strands at the 3’ end, and then joins the viral and cellular DNA strands together, using metals like Mg2+ to carry out these catalytic reactions.
Drug Information:
Schematic figure of drug:
Figure 3) Chemical structure of raltegravir, which is marketed as Isentress. Each point on the hexagons represents a carbon atom unless otherwise shown, the F is a fluorine atom, the N’s are nitrogen atoms, the O’s are oxygen atoms, and the H’s are hydrogen atoms. If a carbon atom only has one bond, it is bonded to six hydrogen atoms (these hydrogen atoms are not depicted). If a carbon atom has a total of three bonds, it is also bonded to two hydrogen atoms. If a carbon atom has a total of four bonds, it is not bonded to any hydrogen atoms. In total, there are 20 carbon atoms, 20 hydrogen atoms, 1 fluorine atom, 6 nitrogen atoms, and 5 oxygen atoms. Formula: C20H20FN6O5 Molecular weight: 482.5 g/mol CAS Number: 518048-05-0 Delivery method: Isentress has three different oral delivery methods: film-coated tablets, chewable tablets for children, and liquid. Side effects: Isentress does not have many adverse reactions, as its most common side effects are insomnia, headaches, dizziness, nausea, and increased creatine kinase levels [10]. Less than 3% of patients taking Isentress report these syndromes [10]. However, individuals who take Isentress rather than other common HIV drugs, like efavirenz, face fewer and less adverse side effects; during the clinical trials of Isentress, only 5% of participants taking Isentress had to stop due to “adverse events,” while 10% of those taking efavirenz stopped their treatment because of harmful side effects [10]. Other names:Raltegravir is patented as Isentress. Maker or company:Merck and Company-a major pharmaceutical company-makes and invented raltegravir. Is it patented?Merck and Company owns one patent for raltegravir under Patent Number 7,169,780 [9]. Clinical Trials Info:Raltegravir went through two double-blind, randomized, and placebo-controlled clinical trials [6]. These trials concluded that the maximum dosage for the liquid is 100 mg twice daily, the maximum dosage for the chewable tablets is 300 mg twice daily, and the maximum dosage for the film-coated tablets is 800 mg twice daily [6]. Of these three delivery methods, only the liquid was found to be suitable for children. Origin:Before researchers at Merck & Company discovered raltegravir as an effective HIV drug, they already knew that 4-Aryl-2,4-diketobutanoic acids (DKAs) inhibit integrase by binding to the metals in integrase’s active site [8]. This inhibition of integrase makes the enzyme non-functional. Because Hepatitis C (HCV) functions similarly to HIV, and DKAs are also used to combat HCV, researchers at Merck used the chemical dihydroxypyrmidine carboxamide that was previously identified as a HCV drug and is a DKA to derive the HIV drug [8]. Using the chemical structure of dihydroxypyrmidine carboxamide, they identified p-flurobenzyl as the most potent residue to combat integrase and gem-dimethyl as the most stable core for the new drug’s structure [8]. This information about the chemical structure of other drugs, the researchers created raltegravir. Alternatives to this drug:Currently, there are more than 25 HIV antiretroviral drugs, in six drug classes [5]. Drug treatments start with three different drugs from two classes, and the combination of drugs prescribed varies depending on each individual [5]. However, raltegravir has been one of the most effective ARV drugs, as 77% of patients who take it decrease the number of the HIV viral load by half compared to those who do not take ARV or take other ARV medications [10]. Miscellaneous:While there are currently many HIV drugs, HIV can still only be treated, not cured. Drugs like raltegravir only kill most HIV-infected cells; a small amount of cells remain dormant and inaccessible to the body’s immune system and ARV drugs [4]. Because of this, once an individual is infected, he will always have HIV, even with proper medication, unless a new method of completely eradicating HIV’s genetic information is found. Goals for HIV prevention and treatment now include increasing access to HIV medication to the areas that need it most, like Sub-Saharan Africa, making new drugs with fewer side effects, and finding a cure to permanently destroy HIV’s DNA. Other uses: can this drug be used to treat other diseases/conditions?No, raltegravir is used only to treat HIV.
Fauci, A.; Pantaleo, G.; Stanley, S.; Weissman, D.; Immunopathogenic mechanisms of HIV infection. Ann of Int Med 1996, 124, (7), 654-663.
Palmisano, L.; Vella, S.; A brief history of antiretroviral therapy of HIV infection: successes and challenges. Ann Ist Super Sanita 2011, 47, (1), 44-8.
Craigie, R.; HIV integrase, a brief overview from chemistry to therapeutics. Jour of Biological Chem 2001, 276, (26), 23213-23216.
Cherepanov, P.; Maertens, G.; Proost, P,; Devreese, B.; Van Beeuman, J.; Engelborghs, Y.; De Clercq, E.; Debyser, Z.; HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. Jour of Biological Chem 2003, 278, (1), 372-381.
Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M., Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008, 51, (18), 5843-55.
Mouscadet J.; Tchertanov, I.; Raltegravir: molecular basis of its mechanism of action. Eur J Med Res 2009, 14, (3), 5-16.
Disease/Drug of interest: Raltegravir and Human Immunodeficiency Virus (HIV)
Motivation and Background:
HIV stands for human immunodeficiency virus and spreads through contact with bodily fluids, such as blood, semen, breast milk, and vaginal liquids, from infected individuals [1]. After HIV initially enters the body, it spreads to the lymphoid tissues through virus replication; if left untreated, HIV begins a period of “microbial latency,” in which it replicates and slowly degrades the body’s immune system [2]. While there are three stages of HIV progression, most patients with HIV are not diagnosed until they reach Stage 3 [1]. In this stage, HIV develops into acquired immunodeficiency syndrome, more commonly known as AIDS [1]. AIDS can develop into many other health conditions, such as pneumonia, thrush, fungal infections, TB, cancer, and brain illnesses, and commonly leads to death, if left untreated [1]. As shown in Figure 1, without any kind of HIV medication, HIV-infected individuals experience about ten years of microbial latency and then die after eleven years upon being initially infected by HIV [3]. HIV is a worldwide problem, as the World Health Organization and Joint United Nations Program on HIV/AIDS estimate that there are 36.9 million people infected with HIV currently, and 39 million people infected with HIV have died since HIV’s discovery in 1981 [4]. Of these numbers, Sub-Saharan Africa adds about 70% of new cases to the worldwide total, 60% of infected people do not have the proper healthcare access to obtain HIV treatment, and 46% do not know that they have HIV, due to inadequate healthcare services [4]. One of the main issues with preventing and treating HIV is that HIV outbreaks are more prevalent in economically disadvantaged areas, so access to HIV diagnosis and treatment is most limited in the areas with the highest rates of HIV infection [4]. Exacerbating this problem, HIV cannot be cured; its symptoms can only be lessened and controlled through the use of antiretroviral therapy [1]. However, antiretroviral therapy is effective at treating HIV symptoms and decreasing the chance of a HIV-related death.Figure 1) Without HIV medication, CD4 T cells deplete by half in six weeks and patients typically die in eleven years.
Of the 6 types of HIV drugs, raltegravir, marketed as Isentress by Merck and Company, introduced the Integrase Strand Transfer Inhibitors (INSTI) category [3]. ARV drugs in this category work by blocking the function of the integrase enzyme [5]. One of raltegravir's major benefits is that it can be taken not only by people who have HIV strains that are resistant to many other pre-existing ARV drugs, but also by those who have just been diagnosed [10].
Target Information:
Size:32 kDa
Location:
Integrase is expressed by HIV's DNA and functions in CD4 T lymphocytes-white blood cells that prevent the body from infections-once it is expressed.
Function in a normal cell:
When this enzyme normally functions, it binds HIV DNA to healthy DNA in a two-step process; first, it separates the viral DNA strands at the 3’ end, and then joins the viral and cellular DNA strands together, using metals like Mg2+ to carry out these catalytic reactions.
Drug Information:
Schematic figure of drug:Figure 3) Chemical structure of raltegravir, which is marketed as Isentress. Each point on the hexagons represents a carbon atom unless otherwise shown, the F is a fluorine atom, the N’s are nitrogen atoms, the O’s are oxygen atoms, and the H’s are hydrogen atoms. If a carbon atom only has one bond, it is bonded to six hydrogen atoms (these hydrogen atoms are not depicted). If a carbon atom has a total of three bonds, it is also bonded to two hydrogen atoms. If a carbon atom has a total of four bonds, it is not bonded to any hydrogen atoms. In total, there are 20 carbon atoms, 20 hydrogen atoms, 1 fluorine atom, 6 nitrogen atoms, and 5 oxygen atoms.
Formula: C20H20FN6O5
Molecular weight: 482.5 g/mol
CAS Number: 518048-05-0
Delivery method: Isentress has three different oral delivery methods: film-coated tablets, chewable tablets for children, and liquid.
Side effects: Isentress does not have many adverse reactions, as its most common side effects are insomnia, headaches, dizziness, nausea, and increased creatine kinase levels [10]. Less than 3% of patients taking Isentress report these syndromes [10]. However, individuals who take Isentress rather than other common HIV drugs, like efavirenz, face fewer and less adverse side effects; during the clinical trials of Isentress, only 5% of participants taking Isentress had to stop due to “adverse events,” while 10% of those taking efavirenz stopped their treatment because of harmful side effects [10].
Other names:Raltegravir is patented as Isentress.
Maker or company:Merck and Company-a major pharmaceutical company-makes and invented raltegravir.
Is it patented?Merck and Company owns one patent for raltegravir under Patent Number 7,169,780 [9].
Clinical Trials Info:Raltegravir went through two double-blind, randomized, and placebo-controlled clinical trials [6]. These trials concluded that the maximum dosage for the liquid is 100 mg twice daily, the maximum dosage for the chewable tablets is 300 mg twice daily, and the maximum dosage for the film-coated tablets is 800 mg twice daily [6]. Of these three delivery methods, only the liquid was found to be suitable for children.
Origin:Before researchers at Merck & Company discovered raltegravir as an effective HIV drug, they already knew that 4-Aryl-2,4-diketobutanoic acids (DKAs) inhibit integrase by binding to the metals in integrase’s active site [8]. This inhibition of integrase makes the enzyme non-functional. Because Hepatitis C (HCV) functions similarly to HIV, and DKAs are also used to combat HCV, researchers at Merck used the chemical dihydroxypyrmidine carboxamide that was previously identified as a HCV drug and is a DKA to derive the HIV drug [8]. Using the chemical structure of dihydroxypyrmidine carboxamide, they identified p-flurobenzyl as the most potent residue to combat integrase and gem-dimethyl as the most stable core for the new drug’s structure [8]. This information about the chemical structure of other drugs, the researchers created raltegravir.
Alternatives to this drug:Currently, there are more than 25 HIV antiretroviral drugs, in six drug classes [5]. Drug treatments start with three different drugs from two classes, and the combination of drugs prescribed varies depending on each individual [5]. However, raltegravir has been one of the most effective ARV drugs, as 77% of patients who take it decrease the number of the HIV viral load by half compared to those who do not take ARV or take other ARV medications [10].
Miscellaneous:While there are currently many HIV drugs, HIV can still only be treated, not cured. Drugs like raltegravir only kill most HIV-infected cells; a small amount of cells remain dormant and inaccessible to the body’s immune system and ARV drugs [4]. Because of this, once an individual is infected, he will always have HIV, even with proper medication, unless a new method of completely eradicating HIV’s genetic information is found. Goals for HIV prevention and treatment now include increasing access to HIV medication to the areas that need it most, like Sub-Saharan Africa, making new drugs with fewer side effects, and finding a cure to permanently destroy HIV’s DNA.
Other uses: can this drug be used to treat other diseases/conditions?No, raltegravir is used only to treat HIV.
References:
- Centers for Disease Control and Prevention. http://www.cdc.gov/hiv/basics/whatishiv.html (accessed Feb 4, 2016).
- Fauci, A.; Pantaleo, G.; Stanley, S.; Weissman, D.; Immunopathogenic mechanisms of HIV infection. Ann of Int Med 1996, 124, (7), 654-663.
- Palmisano, L.; Vella, S.; A brief history of antiretroviral therapy of HIV infection: successes and challenges. Ann Ist Super Sanita 2011, 47, (1), 44-8.
- U.S. Department of Health and Human Services. https://www.aids.gov/hiv-aids-basics/hiv-aids-101/global-statistics/. (accessed Feb 4, 2016).
- National Institute of Health. https://aidsinfo.nih.gov/education-materials/fact-sheets/21/53/what-to-start selecting-a-first-hiv-regimen (accessed Feb 4, 2016).
- Craigie, R.; HIV integrase, a brief overview from chemistry to therapeutics. Jour of Biological Chem 2001, 276, (26), 23213-23216.
- Cherepanov, P.; Maertens, G.; Proost, P,; Devreese, B.; Van Beeuman, J.; Engelborghs, Y.; De Clercq, E.; Debyser, Z.; HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. Jour of Biological Chem 2003, 278, (1), 372-381.
- Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M., Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008, 51, (18), 5843-55.
- Mouscadet J.; Tchertanov, I.; Raltegravir: molecular basis of its mechanism of action. Eur J Med Res 2009, 14, (3), 5-16.
- Isentress [package insert]. Kenilworth, NJ: Merck & Company; 2007. https://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf (accessed Feb 4, 2016).
External links: